The common occurrence and serious outcome of prostate cancer (PCa) skeletal metastases has risen to the forefront of public concern and subsequently the NCI. In the first nine years of this program award, we have addressed this important issue, resulting in over 135-grant-related publications and set groundwork for several clinical trials. In the current competitive renewal, we further attack this problem by combining leading expertise in PCa research and bone biology. The ultimate goal is to define the cellular and molecular mechanisms that surround PCa skeletal metastases to facilitate translation into clinical application. The central theme of this Program is that there is crosstalk between PCa cells and the bone microenvironment that fosters the development and progression of PCa metastasis. This crosstalk promotes the ability of PCa cells to alter the bone microenvironment and render it fertile for tumor growth. To expand on this theme the Program encompasses closely interrelated hypotheses of four scientific projects supported by three cores. Project 1 explores the novel concept that the ability of tumor-associated macrophages (TAMs) to induce PCa cells to undergo epithelial to mesenchymal transition (EMT) is a key mediator of bone metastasis; Project 2 examines the exciting idea that the hematopoietic stem cell (HSC) niche induces disseminated tumor cells (DTCs) to adopt a primitive, phenotype capable of existing in a chemoresistant/dormant state, with the capacity for long-term survival and potential to develop into overt bone metastases; Project 3 explores the surprising role of primary PCa microvesicles in inducing a metabolic state in the distant marrow microenvironment that favors PCa growth; and Project 4 investigates the novel hypothesis that bone marrow macrophages support PCa growth in bone via phagocytosis/efferocytosis of apoptotic tumor cells. These projects will be supported by three integral cores: Core A (Administration) that will coordinate reporting, evaluation, and advisor activities, facilitate interactions among the projects and provide biostatistical support; Core B (Animal) provides mouse models and imaging and assistance with their use and Core C (Bone) provides expertise with bone histology processing, interpretation, and procurement of bone marrow elements. This combination of investigators, projects and cores result in a highly synergistic Program that will continue to provide cutting-edge research and leadership in the field of PCa skeletal metastases.